Mechanisms of endocrine resistance in breast cancer: an overview of the proposed roles of noncoding RNA

Abstract

Endocrine therapies such as tamoxifen and aromatase inhibitors are the standard treatment options for estrogen receptor-positive breast cancer patients. However, resistance to these agents has become a major clinical obstacle. Potential mechanisms of resistance to endocrine therapies have been identified, often involving enhanced growth factor signaling and changes in the expression or action of the estrogen receptor, but few studies have addressed the role of noncoding RNA (ncRNA). Two important types of ncRNA include microRNA (miRNA) and long noncoding RNA (lncRNA). miRNAs are small RNA molecules that regulate gene expression via translational inhibition or degradation of mRNA transcripts, while lncRNAs are larger RNA molecules that have been shown to play a role in multiple cellular maintenance functions such as protein scaffolding, chromatin looping, and regulation of mRNA stability. Both miRNA and lncRNA have recently impacted the field of breast cancer research as important pieces in the mechanistic puzzle of the genes and pathways involved in breast cancer development and progression. This review serves as an overview of the roles of miRNA and lncRNA in breast cancer progression and the development of endocrine resistance. Ideally, future experiments in the field should include identification of ncRNAs that could be potential therapeutic targets in endocrine-resistant tumors, as well as ncRNA biomarkers that facilitate more tumor-specific treatment options for endocrine-resistant breast cancer patients.

miR-155 Drives Metabolic Reprogramming of ER+ Breast Cancer Cells Following Long-Term Estrogen Deprivation and Predicts Clinical Response to Aromatase Inhibitors

“…We therefore explored the molecular components that could be responsible for the metabolic and motile reprogramming that MCF7 cells undergo under LTED conditions and after 2-DG treatment. Deregulation of miRNA expression has been demonstrated in many types of cancer and the involvement of miRNAs has been previously described in breast cancer etiology (42) and in endocrine therapy response and resistance (43). For example, miR-221/222 was able to confer tamoxifen resistance (44), while reexpression of miR-375 (45), let-7 (46), miR-342 (47), or miR-320 (48) induced tamoxifen sensitivity.…”

Recent trends in microRNA research into breast cancer with particular focus on the associations between microRNAs and intrinsic subtypes

“…miRNAs are also associated with resistance to aromatase inhibitors. 60 Masri et al 61 suggested that miR-128a modulates the transforming growth factor-β signaling and survival of letrozole-resistant cell lines. miRNAs expression profiling before and after letrozole treatment reveal post-treatment increases in let-7f expression in both the preclinical and clinical settings.…”

Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3)

“…However, the fundamental clinical challenge associated with this treatment option is the development of resistance to endocrine therapy [2].The mechanisms of resistance have yet to be fully elucidated [2]. Among women with disease progression after prior endocrine therapy, treatment options include sequential endocrinebased therapies, as monotherapy or in combination with a targeted therapy (e.g., everolimus for some postmenopausal women), before switching to chemotherapy [1].…”